Research: Our research group is focused on investigating the genetic basis for human lung cancer and to develop new strategies for clinical trials. We have recently identified the genetic basis for pulmonary mucoepidermoid carcinoma by isolating and cloning the chromosomal breakpoint of a characteristic t(11;19) translocation. To date we have cloned the two novel genes that form a mutant gene fusion protein in these tumors and have shown that this Mect1-Maml2 fusion protein can transform cells by demonstrating that: 1) that Mect1-Maml2 can induce foci formation on rat epithelial cells; 2) transformed foci maintain Mect1-Maml2 protein expression indefinitely without selection in culture and are highly tumorigenic in nude mice and explanted tumors maintain high-level Mect1-Maml2 expression, 3) RNAi inhibition of Mect1-Maml2 induces rapid cell death of mucoepiermoid cancer cell lines that carry the t(11;19) translocation, but show no effect on other primary or tumor cells, and 4) 75% of primary mucoepidermoid cancers obtained from different institutions carry the same Mect1-Maml2 fusion product. We presently have a doxycylcine inducible model for Mect1-Maml2 expression in cells in vitro and for a transgenic mouse model program, and we studying different RNAi agents for preclinical testing. Recent data shows that the Maml2 component is part of an essential co-activator for the NOTCH signaling pathway and the Mect1 component is part of an essential co-activator for cyclic-AMP/CREB signaling. Future work will help define the mechanism of Mect1-Maml2 tumorigenesis and will explore this fusion product as a candidate molecular target for pr-clinical and clinical studies. This project is part of an effort to study the genetic basis of lung cancer in younger patients and we will continue to identify and collect samples from the clinic at the National Naval Medical Center. In addition, we have studied the role of the RB tumor suppressor pathway in human cancer and have demonstrated that the RB/p16 tumor suppressor pathway is inactivated in 100% of small cell lung cancer (SCLC) and non-SCLC. We are currently studying the interrelationships between RB/p16 and the cyclin d/ras pathways. We are also continuing a long-standing project on the functional properties of the RB tumor suppressor protein using mutant alleles isolated from patients with lung cancer and from families linked with the phenotype of incomplete penetrance.